U.S. Pat. No. 5,226,914 (AI Caplan) discloses a method for treating connective tissue disorders by isolating and culturally expanding marrow-derived mesenchymal stem cells, adhering the cells onto the surface of a prosthetic device and implanting the prosthetic device containing the culturally expanded cells into the type of skeletal or connective tissue needed for implantation.
U.S. Pat. No. 5,399,665 (D Barrera) discloses the synthesis and applications of a hydrolytically degradable polymer useful in biomedical applications involving the interaction of cells with the polymer structure, by coupling peptides to the free amino groups of the polymers.
U.S. Pat. No. 5,041,138 (JP Vacanti) discloses methods and artificial matrices for the growth and implantation of cartilaginous structures and surfaces and the production of bioactive molecules manufactured by chondrocytes. Chondrocytes are grown in culture on biodegradable, biocompatible fibrous matrices until an adequate cell volume and density has developed for the cells to survive and proliferate in vivo, and the matrices are designed to allow adequate nutrient and gas exchange to the cells until engraftment and vascularisation at the site of engraftment occurs.
U.S. Pat. No. 5,522,895 (AG Mikos) discloses a biodegradable prosthetic template of a degradable polymer such as poly(lactic acid) or poly(lactic-co-glycolic acid) with a pore-former such as salt or gelatin, which template may be seeded with osteoblasts. The polymers used do not bind to bone and the osteoblasts are highly differentiated cells.
WO 96/28539 proposes a composition for growing cartilage or bone consisting of a biodegradable polymeric carrier such as polyglycolic acid or a polysaccharide containing mesenchymal stem cells. Mesenchymal stem cells are cells which are pluripotent, i.e. which can differentiate to various tissue types (muscle, cartilage, skin), while the polymers proposed do not bind to bone.
These prior art methods involve cells that are grown in the materials for the purpose of expansion or proliferation after which the materials containing the culturally expanded cells, are implanted at the site of engraftment. The prior art materials are degradable matrices, whether or not designed to couple peptides or biologically active moieties to serve to enhance binding of cells to the polymer, that mainly function as temporary devices for cell attachment. These prior methods therefore necessitate the production of connective tissues in vivo, while the prior materials function as a carrier for cell attachment and cell growth.
Surgical procedures related to bone tissue deficiencies vary from joint replacement, bone grafting and internal fixation, to maxillo-facial reconstructive surgery. From a biological perspective, the ideal material to reconstruct osseous tissues is auto-genous bone, because of its compatibility, osteoinductivity, osteoconductivity, and lack of immunologic response. However, the limitations of harvesting an adequate amount of autogenous bone, and the disadvantages of a secondary operation to harvest the auto-logous bone, make this "ideal" material far from ideal for many surgical procedures.
Alternatives are other bone-derived materials and man-made biomaterials. The first group concerns allogeneic and xenogeneic bone grafts. A problem is, that they exhibit the possibility of disease transfer such as HIV or hepatitis B, a higher immunogenic response, less revascularisation of the graft and manifest unreliable degradation characteristics.
The second group concerns man-made, alloplastic implant materials, or bio-materials, which are readily available in large quantities. The wide variety of biomaterials that are used in clinical applications can be divided into four major categories: metals, ceramics, polymers and composites, which all have their own characteristics. The most interesting alloplastic biomaterials for bone replacement are bioactive or osteoconductive materials, which means that they can bind to bone tissue. Bioactive materials can be found in all four of the above mentioned biomaterials categories and include polymers such as PEO/PBT copolymers, calcium phosphate ceramics such as hydroxyapatite and bioglasses or glass-ceramics.
Compared to autogenous bone, the main disadvantage of biomaterials is that, without added osteoinductive agents such as bone morphogenetic proteins, they are not osteoinductive and therefore do not have the ability to actively induce bone formation. Although this can be overcome by adding osteoinductive growth factors to the materials, difficulties still exist to gradually release these factors from the biomaterial surface over a prolonged time period, which is needed to have a sufficient biological response.
This is why there is a need for another approach for the treatment of osseous defects, which combines cultured autogenous tissues with biomaterials, in so-called biomaterial-tissue hybrid structures. Although the combination of cultured cells with biomaterials to form biomaterial-cell composites may also be advantageous in that the cultured cells, after implantation, can give rise to the formation of a tissue, we describe herein an invention of a device in which cells are cultured to produce an extracellular matrix, after which this biomaterial-tissue hybrid is implanted at the site of engraftment.